In cancer, as in politics, everything funnels into the primary. Both,
it should be noted, have about equal rates of success.

Oncologists are direct. Theirs is a ready-aim-fire sort of existence.
They want to know what kind of cancer their patient has—breast,
lung, prostate—so theyll know how to treat it. Had they been in
charge of the last presidential election, it’s easy to imagine them ducking
New Hampshire, the Iowa caucus, and Super Tuesday in favor of something
more streamlined: one primary, one candidate.

Pathologists, on the other hand, could be mistaken for DNC roadies, sharing
a cup of coffee with all the candidates and weighing the merits of Joe
and Carol, the two Johns, Al and Dennis and Howard. Each primary is a
way to sift through issues and possibilities, with the best bet—though
not necessarily the winner—emerging at the end of a long, crisscrossing
march.

Even if pathologists prefer to take the direct route, they can’t always
do so, particularly when it comes to identifying the primary site of a
cancer. In fact, what sounds like a simple question—What kind of
cancer is it?—may never even be answered.

Carcinomas of unknown primary, as they’re commonly called, are troubling.
But not always for the obvious reasons.

One problem is obvious: Some carcinomas have standard and efficacious
therapies, and oncologists want to take advantage of them whenever possible.
From a patient’s perspective, the problem is even more transparent: The
specter of an untraceable cancer has a nightmarish quality to it.

But those problems ignore other, more subtle difficulties. One is age-old:
Oncologists want definitive answers, while pathologists don’t always have
the tools to provide them. And occasionally oncologists may have their
answer without even realizing it, when they fail to obtain a thorough
history and to pass it along to pathologists.

It’s also no secret that even the best chemotherapies are less than perfect.
"If you find an honest oncologist—not that there aren’t any, but
to find one without a particular bias—they’ll tell you there aren’t
that many super effective chemotherapeutic agents," says Andrew L. Folpe,
MD, associate professor, Department of Pathology and Laboratory Medicine,
Emory University Hospital. Oncologists are fond of talking about the various
sensitivities of specific tumors to specific treatments, he notes, "but
they never, in my experience, have much trouble coming up with a regimen
to give a patient when you say, ’I’m not that sure what it is.’"

Speaking by phone from his office in Atlanta, Dr. Folpe says, "I’m sitting
here staring at 150 papers about treating carcinoma of unknown primary
with three specific regimens, and they all seem to combine basically the
same three drugs, as far as I can tell. In fact, as I look, I can see
that they’re overlapping the way they treat lung and the way they treat
urothelial cancers, and a whole bunch of other tumors."

It’s possible, then, that an unknown primary may not be the incubus it
first appears to be. Identifying the primary "often is not hugely important,"
says Dr. Folpe. But while the unknown may not be cataclysmic, it continues
to draw physicians forward, like agnostics on a pilgrimage.

The best place to start, as any married woman knows, is by asking for
directions.

Cases that start out looking like tumors of unknown origin—another
common sobriquet—may have an obvious if overlooked source.

"Pathologists need to make every effort to ensure that there is not a
known history of malignancy," says Richard W. Brown, MD, medical director
of the laboratory at Memorial Hermann Southwest Hospital, Houston, and
chair of the CAP Histotechnology Committee.

Rod Miller, MD, director of immunohistochemistry, ProPath Laboratory
Inc., Dallas, receives his fair share of cases marked as tumors of unknown
origin or unknown primary, on which he then runs a battery of immuno stains.
"But sometimes when the smoke clears, we find out that the clinician just
didn’t tell the pathologist that his patient had a prior history of a
particular tumor. If we know that history ahead of time, we will approach
these cases quite differently." That’s why he encourages pathologists
to make a simple phone call before they start working up these tumors.
"It’s worth a few minutes of your time to ask the clinician whether the
patient has any prior pertinent history that might guide us toward the
most likely primary site," says Dr. Miller, who is also a member of the
CAP Cell Markers Committee.

Those are the easy cases—terra incognita has, in fact, been traveled
before, and the unknown primary is actually hiding in plain sight. The
number of cases initially labeled as "unknown primary" can drop further
as parallel tracks of detection unfold.

It’s a delicate matter, involving the cleft between community and academic
pathology. Dr. Folpe describes cases that arrive from smaller hospitals,
in which "you get the sense that the patient has not been worked up at
all before the pathology was sent out, and the referring pathologist and
referring clinician just haven’t thought it through." As the consulting
pathologist works up the case, the referring physicians may begin to look
into matters more deeply. "Often what happens is when you get back to
them, they’ll say, "Oh yeah, it turns out she’s got a tumor in the ovary."
And your own findings will be consistent with that."

"It appears to be a much bigger problem in community-based practices;
that is, community-based practices tend to send them to reference labs
or academic centers for big immunohistochemical workups," says Dennis
Sgroi, MD, director of breast pathology at Massachusetts General Hospital
and associate professor of pathology at Harvard Medical School. Larger
institutions have extensive IHC facilities; by using a broad panel of
antibodies, pathologists often can reduce the number of "unknown" cases.

But not always. "Often what happens even when they send them out to these
reference labs, reference labs can just say it’s a poorly differentiated
carcinoma," says Dr. Sgroi. "And so you’re back to ground zero. You’d
be surprised at how many they can’t figure out, even after big workups."

The flip side is that community-based pathologists have ample opportunity
to engage with other physicians, a practice that can erode when pathologists
work with multiple hospitals or are completely off-site. "As people get
divorced from having that interaction, between the surgeon, the oncologist,
the pathologist, the radiologist, then we end up doing broader and broader
workups, which are, in my opinion, less effective," says Dr. Folpe. It
may be that finding the primary does indeed require a complex workup,
just as sometimes the best way to reach a destination is to fire up a
GPS device. But sometimes it’s enough to roll down the window and ask
a passerby for directions.

Though estimates vary, it’s generally agreed that cases involving unknown
primaries account for no more than 10 percent of all newly diagnosed malignancies.
Some say that figure may drop to four percent; others say it may be closer
to two or three percent, and still others suggest four to six percent
is a reasonable range.

Allen M. Gown, MD, says these tumors are a staple of the consultation
service at PhenoPath Laboratories, Seattle, where he is medical director
and chief pathologist. His lab sees six to 12 new cases a day of carcinoma
of unknown primary.

Dr. Sgroi considers the problem to be significant, noting that even if
the lower percentages are the more accurate figures, the total numbers
will still be large, given the overall number of cancer diagnoses made
each year. "It’s more common than non-Hodgkin’s lymphoma. It’s one of
the top 10 most common cancer diagnoses," he says.

It’s also the fourth most common cause of cancer mortality, he says.
Why are they so aggressive? "That’s the $64 billion question," Dr. Sgroi
says. "We don’t know. We wish we did. But we don’t." The biology of these
tumors is not well studied. They’re likely not a homogenous group, and
for whatever reason, they have metastasized widely in the absence of a
clinically definable tumor in their site of origin.

Drawing on his own area of expertise, breast cancer, Dr. Sgroi notes
that the tumors that tend to respond to chemotherapy—at least initially—turn
out to be poorly differentiated. That’s not necessarily a surprise, since
these tumors often proliferate rapidly, and certain chemotherapeutic agents
tend to work better when cells are dividing. But overall the outcome is
poor. "You can reduce tumor load, but what’s left is still dividing at
a great rate—that’s the simple way of looking at it," Dr. Sgroi
submits.

Who are these artful dodgers?

Often they’re hepatomas, which can present as either a single mass or
multiple masses in the liver. They can also have a morphologic appearance
that simulates a variety of other tumors, says Dr. Miller. Ovarian tumors
may also have deceptive morphologic appearances that push pathologists
to consider metastatic disease from a number of other, nonovarian primary
sites. Differentiating lung and colon tumors on morphology alone can also
be ticklish—Dr. Miller points to the example of a patient with colon
cancer who presents two years later with a lung nodule. A biopsy reveals
an adenocarcinoma, but the morphology doesn’t reveal its origin.

Small tumors can easily lie in purdah. So can tumors that regress. Some
are tucked away in areas that are difficult to image. Occasionally a primary
tumor site is removed along with the organ—a gallbladder removed
for what is presumed to be benign disease, for example, may contain a
small carcinoma that later shows up in the liver. The primary is now gone—and
was never found in the first place.

Dr. Gown divides cases of unknown primary into two particular carcinomas.
As an example of one category, he describes a woman in her 60s or 70s
who appeared to be disease-free following a breast cancer five or 10 years
earlier but now has a tumor in her lung. The differential is clear and
limited: Is this a new lung primary, or is this a metastasis from the
previous cancer?

In the other category might be a man in his mid-50s who presents with
multiple lesions in the liver. This gives rise to a much more open-ended
question: Where is the primary site?

One subset of "unknown" tumors is somewhat easier to place: primary peritoneal
serous carcinomas in women. These tumors, though akin to ovarian cancer
biologically, spread primarily over the peritoneal surface; they are a
well-recognized category of tumor that scatters widely without having
a so-called tumor mass in a particular organ. "It’s possible that there
are other tumors like this that we have not identified," says Dr. Brown.
"But generally speaking, one assumes in these tumors of unknown primary
that there is a site of origin that you simply can’t identify."

Faced with these varying shades of the unknown, what’s the best way for
pathologists to search for answers?

Pathologists are most effective when there is a defined differential
diagnosis, says Dr. Gown—for example, a patient with a history of
colon cancer presenting with a mass in the ovary. Given that focused differential,
"We have a panel of immunohistochemical markers that can be very effective."
Ditto for cases in which a patient has a tumor in, say, the vicinity of
kidney, adrenal, and liver, prompting the question, Is it adrenal cortical,
renal cell carcinoma, or hepatocellular carcinoma? In these scenarios,
looking for the primary resembles the subtle, skillful motions of fly-casting.

Of course, you can also land a fish by dropping grenades in the water.
"Where we’re least effective is in the setting of, a random lymph node
pops up, it’s an undifferentiated carcinoma histologically, and then we
start to throw in markers," says Dr. Folpe. "My experience has been that
we very, very often end up with a fairly broad differential diagnosis,
even after we’ve done an extensive workup on it. And then it ends up getting
bounced back to the clinicians."

Histology should be the major guide at the beginning of any workup, Dr.
Gown says, but it should not be used to override other evidence, in part
because histological appearances can change as tumors progress. ProPath’s
Dr. Miller, who says nearly all his work is referral from other laboratories,
begins with a thorough review of a standard H&E section. Then, depending
on the tumor’s appearance, he and his colleagues will turn to a panel
of immunostains. Sometimes just a few stains will suffice to let Dr. Miller
narrow down the likely primary site, if not identify it. In other cases,
it may take a dozen or so stains.

The most promising markers to come along in recent years are the so-called
homeobox proteins, or transcription factors, says Dr. Brown. These include
thyroid transcription factor-1, or TTF-1, which is unique to lung and
thyroid, and CDX-2, which is unique to gastrointestinal sites. These proteins
regulate the development of the cell line in normal tissues and are frequently
overexpressed in tumors from those particular sites.

Dr. Folpe reiterates the value of IHC in the context of focused panels.
"In so many settings, we have only a limited number of magic bullets in
terms of the immunos," that is, markers that truly are fairly lineage-specific,
he says. He and his colleagues at Emory usually begin their workups by
looking at a combination of cytokeratin subsets, then move through their
lineage-directed markers. Dr. Folpe catalogs their choices: "We have a
couple of lung markers—TTF-1 and surfactant A. We have markers directed
against mesothelium, but also sort of work for ovarian cancer, such as
WT1. We have a relatively recent marker of enteric tumors, CDX-2. We have
a marker of hepatocellular carcinoma, Hep Par 1. For breast, we have a
marker called gross cystic disease fluid protein-15." Though there may
be one or two others, he says, "the truth is, there aren’t that many more.
There really aren’t good markers for gastric cancers, pancreatic cancers,
biliary cancers, small intestinal carcinomas; breast cancers that are
negative for hormone markers and for gross cystic disease fluid protein-15;
lung cancers that are negative for TTF-1 and surfactant A—and about
20 percent of them will be."

That leaves a "pretty good number of tumors that we can’t do a whole
lot with," Dr. Folpe continues. That’s why clinical correlation is critical.
"That lets you say, ’It’s got a nonspecific phenotype, but that’s OK for
this type of tumor.’ In other words, I’m not seeing anything that’s inconsistent
with a lung primary, for example. So we’re not raising the possibility
of another tumor."

IHC has other limits. Dr. Miller warns of the more common pitfalls. One
is relying on so-called predilute, ready-to-use primary antibodies, "which
I personally think are very dangerous reagents to use in a diagnostic
setting, because in that situation you’re relying on manufacturers to
determine the sensitivity and specificity of the diagnostic laboratory’s
immunostains, a task which is the laboratory’s responsibility, not that
of the manufacturer," he says.

Endogenous biotin artifact, which can occur in tumors with endogenous
biotin, can also trip up unwary pathologists. If pathologists use an avidin/biotin-based
detection system and fail to block the endogenous biotin, tumors will
often light up with unsuspected markers—one imagines an electrifying
grand finale capping what until then has been a docile backyard fireworks
display.

Pathologists should bear in mind the spectrum of reactivity these markers
possess. A new marker is often touted for its specificity, Dr. Miller
notes, but "after it gets out in a number of laboratories and is studied
for a period of time, it very frequently becomes clear that the antibody
is not all that it’s cracked up to be." He sidesteps this problem by using
multitumor tissue controls for all his staining. His routine preparations
contain some 80 different tumors, he explains. When he brings a new antibody
onboard, he optimizes it using those preparations, which lets him stain
80 tumors simultaneously. (He keeps a key to identify the tumors.) He’ll
know within a day or two whether the claims for these new antibodies are
valid.

While IHC remains the workhorse for identifying unknown primaries, there
are times when it’s appropriate to keep it in the barn, so to speak. Patients
with extremely short life expectancy may not benefit from having their
primary identified, says Dr. Miller.

He’s less inclined to accept the objections of those who think a panel
of immunostains is a wasted expense. "There are even pathologists who
suffer from something that I call immunohistochemical guilt," he says,
who are "inappropriately confident in their ability to interpret H&E sections."
Some pathologists do perform like rodeo stars in this arena. "But most
of us normal types of pathologists just can’t tell where these tumors
are coming from, or oftentimes even what kind of tumor it is. And if you
are overconfident at those types of cases, that can lead to problems and
missed diagnoses."

Serum markers are often misleading in cases involving unknown primaries,
cautions Dr. Brown, who adds that many oncologists nevertheless give them
great weight. A woman with a widely metastatic tumor in the abdomen may
have significantly elevated levels of CA-125. That doesn’t necessarily
indicate a primary ovarian or peritoneal cancer; the rise could be due
to irritation of the pelvic peritoneum. Oddly, in many cases there seems
to be no correlation between expression of tumor markers on the tumor
and the serum level. It’s not unusual to find a patient with an elevated
CEA level despite a CEA-negative tumor, or vice versa, Dr. Brown says.

Markers such as PSA remain the exception rather than the rule, adds Dr.
Gown. Indeed, PSA has remained a sort of sangraal for investigators hoping
to find similar serum markers for breast and lung cancers. The search
is far from over, and may still yield results; the advent of molecular
techniques to identify gene products makes that prospect even more likely
than in the past. On the other hand, these other tumors may be more complex
than prostate, upending the promise of serum markers.

There is another possibility for identifying primary sites, though it’s
hardly a rousing one: autopsy.

The difficulty with autopsy, says Dr. Brown, is that when the patient
dies, he or she typically has a widely disseminated malignancy. "At that
point, there is so much tumor burden all over the body, it becomes a guessing
game as to which tumor mass in their body might be bigger than another.
So in my personal experience, and in the literature as well, autopsy is
rarely more successful than the antemortem studies in identifying a primary
site."

Dr. Miller hazards that in 65 percent of the cases, he and his colleagues
can provide clinicians with either a primary site or a short list. "We
can often narrow the list of possibilities substantially," he says.

And when he can’t? Then he turns to face the wall. "I actually have a
list there of all the various primary sites for cancers in the body,"
he says. "And I will specifically address each one of those primary sites
in my comments." He’ll begin by noting he can’t identify the primary site,
then provide a list of the most likely possibilities—say, pancreas,
lung, or stomach. Next, he’s often able to say with conviction that other
tumors are extremely unlikely or excluded—say, kidney, adrenal,
hepatoma, bladder, or prostate. "Even when I can’t tell them precisely
where it’s from, I think we can give them information that will help clinicians
direct their search much more efficiently."

The best piece of advice may be, as it so often is, the easiest to follow:
make better use of what’s available. No one is denying the importance
of the markers developed in recent years. They’re more robust and easier
to use, and they’ve allowed pathologists to improve their work considerably.
"But we do our best job when we begin the process armed with some clinical
information," Dr. Folpe says. "So I would encourage people to wait to
do the big workup until after you’ve got some sense from the oncologist
of what’s going on. Because then you can be a little bit focused."

Ultimately, however, pathologists, like religious leaders, often face
the disquieting prospect of having to respond to unanswerable queries.
"We can assign a tumor, in most cases, to the broad category of a carcinoma
versus, say, metastatic melanoma or lymphoma," Dr. Brown says. "But within
the category of carcinoma, identifying the organ of origin is in many
cases not successful." In many cases, he concedes, "We do not definitively
answer the question."

That doesn’t sit well with clinicians. "I think the biggest misconception
among oncologists is that we can tell in every case where the tumor’s
coming from," Dr. Brown says. "It’s a great source of frustration on both
sides."

No matter how hard oncologists continue to press for a specific answer,
pathologists will continue to fall short. "We’re probably at the limits
of what we can do with IHC," says Dr. Brown. Molecular profiling, in his
opinion, is the Next Big Thing—the focus of much current research
and the likely choice to pull pathologists past the IHC border. But depending
on your point of view, microarrays may be both as significant and as everlasting
as the Peace of Westphalia.

Dr. Sgroi, who’s done extensive research in gene expression profiling,
predicts the method will surpass IHC, if for no other reason than it allows
pathologists to look at a much larger number of variables than with IHC.
While microarrays are not a shoo-in, many of the problems associated with
them have been worked out in recent years, Dr. Sgroi says. And their use
in identifying primary tumor sites appears to be a fairly straightforward
application. "It’s not completely pie-in-the-sky," he says. Gene expression
platforms may also be more cost-effective than IHC workups, he adds.

For all his enthusiasm, Dr. Sgroi is careful to temper his predictions
by stating his strong support of IHC, calling it "very, very useful" and
noting that he uses it "all the time." But, he says, "I think there are
cases in which the gene expression platform may give you a higher probability
of figuring out where the tumor comes from."

Dr. Folpe is a bit skeptical. He suggests that the genes being identified
with microarray techniques are no different from the proteins that pathologists
currently identify using IHC. "There’s not any real magic in what they’re
doing. I think they make it sound sexy because it’s ’microarray’—it’s
got a certain sort of sexy quality to it."

The premise is certainly reasonable, he says—it makes infinite
sense that a lung tumor would have a molecular signature that would differ
from the molecular signature of a colon tumor. "What I’m unclear about,"
says Dr. Folpe, "is whether we can sort through all the noise and all
the genes that are up and down and sideways in a met. Can we sort out
the important pieces of information to say, ’This is lung and not colon’?
My guess is there’s an immense amount of overlap in the gene expression
profiles."

Dr. Gown suggests the best bet may be their selective use to identify
primary sets of tumors. Even more likely, he says, gene expression array
data may be used to identify target genes; from there, appropriate antibodies
can then be found. Because IHC is such a powerful technique, blending
phenotypic and morphologic information may supplant molecular techniques,
as has happened in the case of diffuse large B-cell lymphoma.

No one, least of all patients, is comfortable with unknown primaries.
Dr. Folpe is the first to admit, "You’d like to find these things."

But there’s an edge to the obvious. As Dr. Folpe puts it, "In a perfect
world, and maybe 30 years from now, when we have chemotherapeutic agents
that are perhaps more tissue-specific, it will matter more. But I would
say for the most part, at this point, it doesn’t matter much."

He doesn’t stop there. One could make the argument, Dr. Folpe says, that
finding the primary may become less, rather than more, important. Chemotherapy
is becoming less concerned with tumor type and more focused on protein
expression—witness c-Kit and gastrointestinal stromal tumors. There’s
also plenty of interest in epidermal growth factor receptor and HER2/neu.
"We’re increasingly being asked to look at those in a wide variety of
different primary sites, and there again, there’s more interest in whether
the tumor has EGFR expression and less interest in whether it’s gastro
or lung. Once we’re given the tumor in the lymph node, I can do an immunohistochemical
test to see whether the tumor’s positive for EGFR. And if it is, they’ll
know how to treat the patient," says Dr. Folpe. "They don’t care where
it came from"—not unlike music buffs who download tunes to their
iPods without ever owning the disc.

Given all that, it’s not unreasonable to wonder whether making fine primary
distinctions will always matter. "I think it could go either way," Dr.
Folpe says. Just like many elections.